A Physiology-Informed Digital Twin Framework for Simulating Liver Health Progression

Human health is a continuous, dynamic trajectory shaped by the cumulative interplay of biological processes, clinical events, behaviors and environmental exposures across the life course. Unifying the full breadth of lifelong health information, including longitudinal records, genetic variation, molecular profiles and environmental histories, is essential for whole-person modeling and remains a major challenge. We introduce LifeLong Digital Twin, a unified, event-driven modeling paradigm that organizes Life Events into daily Health States and accumulates them into Lifelong Health Context. An accompanying Agent Harness incorporates multimodal evidence beyond the language model's textual context. We evaluate four language models across 25 disease endpoints on three tasks: Disease Trajectory Forecasting, Disease Risk Ranking and Multi-horizon Disease Prediction. The approach yields marked gains over the reference condition: model-averaged F1 increases by 22.0% for disease identification in trajectory forecasting and 18.3% for five-year disease outcomes; thyroid-disease F1 reaches 0.669. The framework provides a foundation for whole-person digital twins and research on personalized lifelong disease prevention.

Understanding how human health changes over time, and why responses to interventions vary between individuals, remains a central challenge in medicine. Here we present HealthFormer, a decoder-only transformer that models the human physiological trajectory generatively, by training on data from the Human Phenotype Project, a multi-visit cohort of over 15,000 deeply phenotyped individuals. We tokenise each participant's health trajectory across 667 measurements spanning seven domains: blood biomarkers, body composition, sleep physiology, continuous glucose monitoring, gut microbiome, wearable-derived physiology, and behaviour and medication exposure. We train HealthFormer to forecast individual physiological trajectories across these domains, and from this single generative objective a range of clinically relevant tasks can be expressed as queries on the model. We show that, without task-specific training, HealthFormer transfers to four independent cohorts and improves prediction for 27 of 30 incident-disease and mortality endpoints, exceeding established clinical risk scores in every comparison. We further show that the model can simulate interventions in silico: in a held-out personalised-nutrition trial, intervention-conditioned predictions recover individual six-month biomarker changes (e.g., Pearson r = 0.78 for diastolic blood pressure). Across 41 randomised intervention-outcome comparisons drawn from published trials, our results show that the predicted direction of effect agrees in every case, and the predicted mean falls within the reported 95% confidence interval in 30 cases. We position HealthFormer as an initial health world model, from which forecasting, risk stratification, and intervention-conditioned simulation arise as queries, providing a basis for clinical digital twins.

This paper presents a proof-of-concept digital twin framework for simulation-driven diabetes modeling using benchmark clinical data, synthetic temporal augmentation, and illustrative continuous glucose monitoring (CGM) analysis. Unlike traditional predictive models, the framework focuses on generating interpretable simulated trajectories rather than clinically validated outcomes. Evaluation is conducted using a public dataset combined with controlled synthetic scenarios to illustrate temporal behavior and intervention effects. Results illustrate the feasibility of integrating prediction with counterfactual simulation for decision-aware analysis. This work does not claim clinical readiness but provides a foundation for future research on simulation-driven digital twin systems in healthcare.